Chapter 21. Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution Reactions

Based on McMurry’s Organic Chemistry, 6th edition

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Carboxylic Compounds Acyl group bonded to Y, an electronegative atom or

leaving group

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General Reaction Pattern

Nucleophilic acyl substitution

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21.1 Naming Carboxylic Acid Derivatives Acid Halides, RCOX

Derived from the carboxylic acid name by replacing the -ic acid ending with -yl or the -carboxylic acid ending with –carbonyl and specifying the halide

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Naming Acid Anhydrides, RCO2COR'

If symnmetrical replace “acid” with “anhydride” based on the related carboxylic acid (for symmetrical anhydrides)

From substituted monocarboxylic acids: use bis- ahead of the acid name

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Naming Amides, RCONH2

With unsubstituted NH2 group. replace -oic acid or -ic acid with -amide, or by replacing the -carboxylic acid ending with –carboxamide

If the N is further substituted, identify the substituent groups (preceded by “N”) and then the parent amide

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Naming Esters, RCO2R

Name R’ and then, after a space, the carboxylic acid (RCOOH), with the “-ic acid” ending replaced by “-ate”

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21.2 Nucleophilic Acyl Substitution

Carboxylic acid derivatives have an acyl carbon bonded to a group Y that can leave

A tetrahedral intermediate is formed and the leaving group is expelled to generate a new carbonyl compound, leading to substitution

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Relative Reactivity of Carboxylic Acid Derivatives Nucleophiles react more readily with unhindered carbonyl groups More electrophilic carbonyl groups are more reactive to addition (acyl

halides are most reactive, amides are least) The intermediate with the best leaving group decomposes fastest

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Substitution in Synthesis We can readily convert a more reactive acid

derivative into a less reactive one Reactions in the opposite sense are possible but

require more complex approaches

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General Reactions of Carboxylic Acid Derivatives water ˝ carboxylic acid alcohols ˝ esters ammonia or an amine ˝ an amide hydride source ˝ an aldehyde or an alcohol Grignard reagent ˝ a ketone or an alcohol

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21.3 Nucleophilic Acyl Substitution Reactions of Carboxylic Acids Must enhance reactivity Convert OH into a better leaving group Specific reagents can produce acid chlorides,

anhydrides, esters, amides

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Conversion of Carboxylic Acids into Acid Chlorides Reaction with thionyl chloride, SOCl2

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Mechanism of Thionyl Chloride Reaction Nucleophilic acyl substitution pathway Carboxylic acid is converted into a chlorosulfite

which then reacts with chloride

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Conversion of Carboxylic Acids into Acid Anhydrides Heat cyclic dicarboxylic acids that can form five- or

six-membered rings Acyclic anhydrides are not generally formed this way

- they are usually made from acid chlorides and carboxylic acids

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Conversion of Carboxylic Acids into Esters Methods include reaction of a carboxylate anion with

a primary alkyl halide

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Fischer Esterification Heating a carboxylic acid in an alcohol solvent

containing a small amount of strong acid produces an ester from the alcohol and acid

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Mechanism of the Fischer Esterification The reaction is an acid-catalyzed, nucleophilic acyl

substitution of a carboxylic acid When 18O-labeled methanol reacts with benzoic acid,

the methyl benzoate produced is 18O-labeled but the water produced is unlabeled

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21.4 Chemistry of Acid Halides Acid chlorides are prepared from carboxylic acids by

reaction with SOCl2 Reaction of a carboxylic acid with PBr3 yields the acid

bromide

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Reactions of Acid Halides Nucleophilic acyl substitution Halogen replaced by OH, by OR, or by NH2

Reduction yields a primary alcohol Grignard reagent yields a tertiary alcohol

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Conversion of Acid Halides to Esters Esters are produced in the reaction of acid chlorides react with alcohols

in the presence of pyridine or NaOH The reaction is better with less steric bulk

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Aminolysis: Conversion of Acid Halides into Amides Amides result from the reaction of acid chlorides with NH3, primary

(RNH2) and secondary amines (R2NH) The reaction with tertiary amines (R3N) gives an unstable species that

cannot be isolated HCl is neutralized by the amine or an added base

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Reduction: Conversion of Acid Chlorides into Alcohols LiAlH4 reduces acid chlorides to yield aldehydes and

then primary alcohols

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Formation of Ketones from Acid Chlorides

Reaction of an acid chloride with a lithium diorganocopper (Gilman) reagent, Li+ R2Cu

Addition produces an acyl diorganocopper intermediate, followed by loss of RCu and formation of the ketone

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21.5 Chemistry of Acid Anhydrides

Prepared by nucleophilic of a carboxylate with an acid chloride

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Reactions of Acid Anhydrides

Similar to acid chlorides in reactivity

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Acetylation Acetic anhydride forms acetate esters from

alcohols and N-substituted acetamides from amines

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21.6 Chemistry of Esters Many esters are pleasant-smelling liquids: fragrant

odors of fruits and flowers Also present in fats and vegetable oils

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Preparation of Esters Esters are usually prepared from carboxylic acids

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Reactions of Esters Less reactive toward nucleophiles than are acid

chlorides or anhydrides Cyclic esters are called lactones and react similarly to

acyclic esters

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Hydrolysis: Conversion of Esters into Carboxylic Acids An ester is hydrolyzed by aqueous base or aqueous

acid to yield a carboxylic acid plus an alcohol

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Mechanism of Ester Hydrolysis Hydroxide catalysis via an addition intermediate

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Evidence from Isotope Labelling 18O in the ether-like oxygen in ester winds up

exclusively in the ethanol product None of the label remains with the propanoic acid,

indicating that saponification occurs by cleavage of the C–OR bond rather than the CO–R bond

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Acid Catalyzed Ester Hydrolysis The usual pathway is the reverse of the Fischer

esterification

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Aminolysis of Esters Ammonia reacts with esters to form amides

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Reduction: Conversion of Esters into Alcohols Reaction with LiAlH4 yields primary alcohols

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Mechanism of Reduction of Esters

Hydride ion adds to the carbonyl group, followed by elimination of alkoxide ion to yield an aldehyde

Reduction of the aldehyde gives the primary alcohol

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Partial Reduction to Aldehydes

Use one equivalent of diisobutylaluminum hydride (DIBAH = ((CH3)2CHCH2)2AlH)) instead of LiAlH4

Low temperature to avoid further reduction to the alcohol

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21.7 Chemistry of Amides Prepared by reaction of an acid chloride with

ammonia, monosubstituted amines, or disubstituted amines

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Basic Hydrolysis of Amides Addition of hydroxide and loss of amide ion

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Reduction: Conversion of Amides into Amines Reduced by LiAlH4 to an amine rather than an alcohol Converts C=O CH2

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Uses of Reduction of Amides Works with cyclic and acyclic Good route to cyclic amines

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21.8 Thioesters and Acyl Phosphates: Biological Carboxylic Acid Derivatives

Nucleophilic carboxyl substitution in nature often involves a thioester or acyl phosphate

These have unique binding properties and are readily activated by enzymes

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21.9 Polyamides and Polyesters: Step-Growth Polymers Reactions occur in distinct linear steps, not as chain

reactions Reaction of a diamine and a diacid chloride gives an

ongoing cycle that produces a polyamide A diol with a diacid leads to a polyester

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Polyamides (Nylons) Heating a diamine with a diacid produces a

polyamide called Nylon®

Nylon 66® is from adipic acid and hexamethylene-diamine at 280°C

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Polyesters The polyester from dimethyl terephthalate and

ethylene glycol is called Dacron® and Mylar® to make fibers

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21.10 Spectroscopy of Carboxylic Acid Derivatives Infrared Spectroscopy

Acid chlorides absorb near 1800 cm1

Acid anhydrides absorb at 1820 cm1 and also at 1760 cm1

Esters absorb at 1735 cm1, higher than aldehydes or ketones

Amides absorb near the low end of the carbonyl region